Radioisotope Concentrator

Overview

Figure 1: (A) Cartridge-based method for concentration. Using an HPLC injection valve with small internal volume, the flow path can be configured in trapping mode, where the [F-18]fluoride/[O-18]H2O is flowed through a micro-cartridge and the [F-18]fluoride trapped, or a release mode, where a small volume of eluent solution is passed through the cartridge to release the [F-18]fluoride and deliver it onto the chip. (B) Scheme for evaporative concentration of [F-18]fluoride radioisotope on chip. The top images show cross-section schematics of the concentration process, and the bottom images show Cerenkov (radioactivity) images of the top-view of the chip at corresponding times. Orange lines and circles were added to depict the cover plate edge and the reaction site, respectively. Initially, a 200 μL droplet of [F-18]fluoride solution is loaded to the cover plate edge. By activating a nearby heater, the volume of the droplet is reduced to ~5 µL, and then pulled into the chip by electrode actuation.

Due to their compact size and small operating volumes, batch microfluidic devices for radiochemistry (e.g. electrowetting on dielectric) offer significant benefit for the synthesis of short-lived radiotracers and could form the basis of a benchtop instrument for on-demand tracer production.
When considering using small reaction volumes, one must also
consider how to produce sufficient quantity (radioactivity) of the tracer for
the particular application needed. For preclinical imaging, generally a few mCi
is sufficient for a study involving several animals, and with modern scanners, <25-50
µCi is sufficient for a single
mouse. On the other hand, imaging of a single patient requires on the order of
10 mCi, while producing a large batch in a radiopharmacy for distribution to
imaging centers would require 100s-1000s of mCi. Even higher amounts of the
radioisotope are needed at the beginning of the synthesis due to non-ideal
yields and fluid handling, as well as losses due to decay.

Cyclotrons can readily generate multiple Ci levels of [18F]fluoride in [18O]H2O
to satisfy any of these applications. However, the output volume is typically
in the milliliter range, while the capacity of the current EWOD chip (12 mm
diameter reaction zone x 150 µm
droplet height) is only ~17 µL,
i.e. 1% of the volume from the cyclotron. From a high-radioactivity
bombardment, it would be possible to load as much of tens of mCi of radioisotope
into the chip without special measures, but it is not desirable to waste the
majority of the radioisotope, and several methods for efficiently concentrating
the radioisotope have been developed.

Results

One approach is to concentrate the [18F]fluoride
prior to loading it into the chip via a solid-phase extraction (SPE) process.
First, the [18F]fluoride/[18O]H2O is flowed
through a strong-anion exchange cartridge (e.g., quaternary methyl ammonium,
QMA) to trap the [18F]fluoride. After removing residual water (e.g.
with an inert gas flow), an eluent solution (e.g. aqueous K2CO3/
K2.2.2 or tetrabutylammonium bicarbonate (TBAB), sometimes with MeCN)
is passed through the cartridge to release the [18F]fluoride. If the
cartridge has sufficiently small bed volume, the volume of eluent solution
needed to efficiently collect the [18F]fluoride can be quite low. Our group and others have shown efficient concentration of at least Ci-levels of [F-18]fluoride into volumes as small as 5-10 µL. We have developed an automated system for preparing concentrated [F-18]fluoride that can be loaded onto microfluidic chips.

A different approach is to perform the [18F]fluoride concentration directly on chip. Using a special chip where the bottom plate extended beyond the edge of the cover plate
to create a platform. A large droplet of [18F]fluoride solution
(with phase transfer catalyst) was loaded onto this platform adjacent to the
gap between the two EWOD chip plates and then rapidly evaporated down to a
small volume that could be transported between the plates. This approach has the advantage of not
requiring any valves, but the disadvantage of requiring larger chip real
estate.

Current Status and Next Steps

The cartridge-based concentrator is in routine use in the laboratory for radiosynthesis at small volumes scales and one has been installed at Harvard Medical School / Masssachusetts General Hospital for clinical production of [F-18]5-FU.